Adrenergic Pharmacology Lecture 2024 PDF

Adrenergic pharmacology Dr.Leila Alblowi 2024 Lecture Objectives : ▪ Understand the synthesis, storage, release, and metabolism of catecholamines. ▪ Identify the physiological effects mediated by adrenergic receptors (alpha and beta). ▪ Examine the mechanisms of action of adrenergic agonists and...

Adrenergic pharmacology Dr.Leila Alblowi 2024 Lecture Objectives : ▪ Understand the synthesis, storage, release, and metabolism of catecholamines. ▪ Identify the physiological effects mediated by adrenergic receptors (alpha and beta). ▪ Examine the mechanisms of action of adrenergic agonists and antagonists. ▪ Explore the therapeutic uses and side effects of drugs that modulate adrenergic neurotransmission. Adrenergic pharmacology It involves the study of agents that Physiologic Effects Mediated by act on pathways mediated by the Catecholamines endogenous catecholamines: 1.Cardiac Function: Increase in Rate and Force Norepinephrine 2.Vascular System: Modification of Peripheral Resistance Epinephrine 3.Insulin Regulation: Inhibition of Insulin Dopamine Release 4.Glucose Metabolism: Stimulation of Hepatic Glucose Release 5.Lipid Metabolism: Increase in Free Fatty Acids  Adrenergic pharmacology Adrenergic drugs target Two groups of drugs that affect the catecholamines neurotransmitter sympathetic nervous system: 1.Adrenergic agonists, Sympathomimetics or Synthesis adrenomimetics Storage 2.Adrenergic blockers, Sympatholytics, adrenolytics Reuptake Metabolism Directly targeting the postsynaptic receptors Adrenergic pharmacology Drugs act on adrenergic neurotransmission Adrenergic agonists Adrenergic antagonists (sympathomimetic) (Sympatholytic) (direct-acting agonists) (indirect-acting agonists) Block adrenergic Activate adrenergic -Enhancing release of norepinephrine receptors receptors -Block reuptake of norepinephrine -Inhibit the degradation of epinephrine or norepinephrine Block norepinephrine synthesis, storage or release Synthesis and Metabolism of NE Synthesis Origin: Dopamine, norepinephrine (NE), and epinephrine are synthesized from sequential chemical modifications of the amino acid tyrosine NE is synthesized from dopamine in the adrenergic nerve terminals, and is transported into storage vesicles Synthesis and Metabolism of NE ▪ Release of NE: ▪ Ca2+dependent exocytosis: Action potential → opens voltage-dependent Ca2+ channel Ca2+ influx →fusion of vesicular and cell membranes NE is released by exocytosis and acts on adrenoreceptors (alpha and beta) Then NE is reuptake again or enzymatically destroyed By: 1- Catechol-o-methyltransferase (COMT) 2- Monoamine Oxidase (MAO) Synthesis and Metabolism of NE Uptake: Uptake-1: The action of released NE is primarily terminated by the Uptake-1 Na+-dependent transporter which couple spontaneous Na+ influx to uptake of NE or Dopamine back into the nerve terminals NE or dopamine is then taken-up into storage vesicles by a vesicular monoamine transporter (VMAT) Uptake-2: NE that diffuses away from the nerve terminal can be taken up by Uptake-2 into postjunctional cells of organs, and be enzymatically destroyed there Synthesis and Metabolism of NE Metabolism: 1- MAO: Is a mitochondrial enzyme (intraneuronal) existing in two isoforms, MAO-A and MAO-B MAO-A: specially degrades serotonin, NA and dopamine MAO-B: degrades dopamine more rapidly than serotonin and NA 2- COMT: is cytosolic enzyme (postsynaptic) Drugs that effect NE synthesis and Metabolism Storage Reuptake Release Metabolism Reserpine bind Cocaine inhibit Guanethidine MAOI, tightly to VMAT transporter can decrease monoamine Resulting in involve in uptake the release of oxidase vesicles lose of NE(Uptake-1), NE from the inhibitors, their ability to allowing NE to adrenergic prevent the concentrate and remain in the storage vesicles degradation of store Ep and synaptic cleft for catecholamine Dopamine a longer period →→ ↑NE, of time, causing dopamine, and increased blood serotonin pressure and central stimulation  Adrenergic Receptors (Adrenoceptors) Three main receptors are: 1. Alpha1 (α1) Each of the adrenergic receptor subtypes is 2. Alpha2 (α2) a member of the G protein-coupled 3. Beta (β) receptor (GPCR) superfamily Each of these major classes has three subtypes: α1A, α1B, α1D α2A, α2B, α2C β1, β2, β3  α1 and α2 Adrenoceptors α1-Receptors express in: α2-Receptors are found on: ✓ Vascular smooth muscle ✓ Both presynaptic neurons and ✓ Genitourinary tract smooth muscle postsynaptic cells (( α2-receptors function ✓ Intestinal smooth muscle to mediate feedback inhibition of ✓ Prostate sympathetic transmission)) ✓ Brain ✓ Platelets: mediate platelet aggregation ✓ Heart ✓ Pancreatic β-cells: inhibit insulin ✓ Liver and Other cell types release  α1 and α2 -Adrenoceptors α1 Receptors α2 Receptors Location: Postsynaptic (effector Location: pre- and post-synaptically, but organs). their main function is typically presynaptic. Function: Classic α-adrenergic effects Function: Controls the release of (e.g., constriction of smooth muscle). norepinephrine. Mechanism: Mechanism: Activation of α1 receptors → Stimulation of α2 receptors → Feedback Activation of phospholipase C → inhibition → Inhibits further release of Increase in DAG and IP3 → norepinephrine(inhibitory autoreceptors). Increase in intracellular calcium. → Muscle contraction Activation of α2 receptors → Inhibition of adenylyl cyclase → Decrease in cAMP → Inhibition of neuronal Ca2+ channels  Alpha receptor location and effect (+) α1→ VC, ↑BP, blood flow is decrease to vital organs (+) α2 → inhibit release of NE, VD, ↓BP α1 α2  β-Adrenoceptors β-Adrenoceptors are divided into three subclasses: β1 β2 β3 All three subclasses activate a stimulatory G protein, Gs Gs activates adenylyl cyclase → Increased intracellular cAMP → Activation of protein kinases → Phosphorylation and activation of a variety of intracellular proteins including ion channels and transcription factors  β1-Adrenoceptors β1-Adrenoceptors are localized primarily in the: β1 ▪ Kidney: (+) Renin release ▪ Heart: (+) of cardiac causes an increase in both: Heart Kidney Inotropy (force of contraction) HR chronotropy (heart rate) renin secretion Heart contraction Angiotensin Blood pressure  β2-Adrenoceptors β2-Adrenoceptors are expressed: β2 1. Smooth muscle (lung, uterine ) 2. Liver 3. Skeletal muscle Smooth Skeletal smooth Liver 4. Heart muscles muscles (+) Activation β2 → ✓ Relaxation of lung smooth ms.(bronchodilation) Relaxation Blood flow Activation of to Sk.ms glycogenolysis ✓ ↑blood flow to skeletal ms. ✓ Relaxation of uterine ms. Blood sugar  β2-Adrenoceptors β2 Smooth muscles Lung Uterus GIT Blood vessels Relaxation of GIT tone and Bronchodilation Vasodilation uterine S.ms motility  β3-Adrenoceptors β3-Adrenoceptors are expressed in: Adipose tissue β3 GIT (+) β3→→ ✓ Increase lipolysis in adipocytes Adipose tissue ✓ Decrease in GIT motility Lipolysis Receptor Agonists Adrenergic pharmacology Drugs act on adrenergic neurotransmission Adrenergic Adrenergic agonists antagonists (sympathomimetic) (Sympatholytic) (indirect-acting agonists) Block adrenergic (direct-acting agonists) -(+) release of norepinephrine -- receptors Activate adrenergic Amphetamine receptors-- epinephrine (-)reuptake of norepinephrine-- or norepinephrine Cocaine -(-) metabolism of epinephrine or norepinephrine--MOI Block NA synthesis, storage or release Mixed-action agonists: Both stimulate adrenoceptors directly and release norepinephrine from the adrenergic neuron -- Ephedrine  Direct-acting sympathomimetics Class Action Example Mixed agonist ▪ β1=β2= α1 = α2 ▪ Epinephrine ▪ β1=α1 = α2 ▪ Norepinephrine α-selective agonist ▪ α2 ▪ Clonidine and methyldopa ▪ α1 ▪ Phenylephrine β-selective agonist ▪ β1=β2 ▪ Isoproterenol ▪ β1 ▪ Dobutamine ▪ β2 ▪ Salbutamol (albuterol)  Physiologic and Pharmacologic Effects of Endogenous Catecholamines Epinephrine Is an agonist at both α- and β-adrenoceptors At low concentrations, has predominantly β1 and β2 effects At higher concentrations, its α1 effects become more pronounced  Physiologic and Pharmacologic Effects of Endogenous Catecholamines Epinephrine ▪ Acting at β2-receptors: ▪ Acting at β1-receptors: Vasodilation → Decrease in peripheral +ve chronotropic effect (↑ HR) and +ve inotropic resistance → Decrease in diastolic BP effect (↑ force of contraction) >increase cardiac ↑ Blood flow to skeletal muscle output> β1 action. Bronchodilation Increase renin release > increase angiotensin II Promotes glycogenolysis (vasoconstrictor) > β1 action. ↑ Glucose and free fatty acids in the blood These β1 and β2 effects are all components of the “fight-or-flight” response  Epinephrine ▪ It is ineffective orally due to extensive first pass metabolism (metabolized by COMT post-synaptically and by MAO ) ▪ It has a rapid onset of and brief duration of action when injected intravenously  Epinephrine Uses : 1. It is the drug of choice for the treatment of anaphylaxis Epinephrine can be given by IM injection to activate adrenoceptors: ✓ α1 (vasoconstriction to ↑ BP and ↓ secretion and Anaphylaxis: edema in mucous membrane) An allergic reaction leading to the release of allergy ✓ β1 (↑ cardiac contractility) mediators such as histamine and leukotrienes. ✓ β2 (bronchodilatation) This can result in symptoms like hypotension, bronchospasm, and increased respiratory tract secretions. Patients who are at risk of developing anaphylaxis should carry an epinephrine autoinjector (EpiPen) for emergency use.  Epinephrine Uses : 2. It is often used in combination with local anaesthetic in dentistry because locally injected epinephrine causes VC and prolongs the action of local anaesthetics 3. Cardiac arrest and heart block  Physiologic and Pharmacologic Effects of Endogenous Catecholamines Norepinephrine ❖ It is an agonist at alpha-1 and beta-1 receptors, but has relatively little effect at beta-2 receptors ❖ Systemic administration of norepinephrine : ↑Systolic BP (Beta-1 effect) ↑Diastolic BP (increase in the total peripheral resistance) Indicated in the treatment of: ✓ Hypotension in patient with sepsis  Amphetamine Amphetamine is classified as an adrenergic stimulant Has several adrenergic actions: 1. It displace endogenous catecholamines from storage vesicles 2. It blocks catecholamine reuptake 3. It is a weak MAOI →→ Enhance NE and Dopamine effects 4. Is a major drug of abuse Uses: 1. Attention deficit hyperactivity disorder (ADHD), can increase attention span of children 2. Suppress appetite  Monoamine Oxidase Inhibitors (MAOIs) They prevent metabolism of catecholamine In the absent of metabolism, more catecholamine accumulates in presynaptic vesicles for release during each action potential Uses: 1. Depression 2. Parkinson’s disease E.g., Selegiline Severe and often unpredictable side effects due to drug-food and drug-drug interactions limit the widespread use of MAO inhibitors  Monoamine Oxidase Inhibitors (MAOIs) E.g., Tyramine, which is contained in certain foods, such as: ✓ Aged cheeses ,Meats ,Chicken liver ,Pickles ,Smoked fish ,Red wines Tyramine is normally inactivated by MAO in the gut Individuals receiving an MAO inhibitor are unable to degrade tyramine obtained from the diet Tyramine causes the release of large amounts of stored catecholamines from nerve terminals, resulting in: ✓ Headache, Nausea ✓ Tachycardia, cardiac arrhythmias ✓ Hypertension ✓ Seizures and possibly Stroke Patients must be educated to avoid tyramine-containing foods  α1-selective agonist Phenylephrine: ▪ Decongestion and Ophthalmology Is given orally or by nasal drops to vasoconstrict the mucous membrane to relieve nasal congestion due to hay fever or common cold Phenylephrine is topically applied to the eye to cause mydriasis to allow view of the retina  α2-selective agonist Clonidine or α-Methyldopa ▪ Antihypertensive ▪ Methyldopa is drug of choice for management of hypertension in pregnancy, where it has a record of safety ▪ Can reduce blood pressure by: ✓ ↓sympathetic outflow from the CNS ✓ ↓release of norepinephrine (peripheral presynaptic action) ✓ VD → ↓BP  non-selective β-agonist Isoproterenol This drug: ✓ ↓ Peripheral vascular resistance and ↓diastolic BP by (+)β2-adrenoceptor ✓ ↑ HR, ↑Force if cardiac contraction by (+) β1- adrenoceptor Use occasionally to stimulate HR in emergency situations of profound bradycardia  β1-selective agonist Dobutamine Selectively agonist for beta-1 adrenoceptor causing: ▪ (+) HR ▪ (+) Cardiac contraction ▪ (+) ↑Cardiac output Use: 1. Urgent treatment of severe heart failure 2. Diagnostic agent, in investigation of ischemic heart disease  β2-selective agonist ❖ Short-acting β2 agonist (SABA): Salbutamol (Albuterol) ▪ Asthma ▪ can be given by inhalation ▪ Quick relief of bronchospasm in asthma (PRN) ❖ Long-acting β2 agonist (LABAs): Salmeterol and formoterol ▪ Long-term control of asthma  Common side effects of adrenergic agonist α1: Hypertensive crisis, cerebral hemorrhage α2: sedation, dry mouth β1: ↑heart rate, cardiac arrhythmias, angina β2: skeletal ms tremor Receptor Antagonists  Adrenergic Blockers Drugs that block the effects of the adrenergic neurotransmitter They antagonises to adrenergic agonists by blocking the alpha and beta receptor sites They are among the most widely used drugs in clinical practice They can act: 1. Directly by occupying the receptors 2. Indirectly by inhibiting the release of the neurotransmitters NE and E (adrenergic neuron blockers)  Effects of Adrenergic Blocking at receptors Report Response Alpha 1 Vasodilation: ↓BP, reflex tachycardia Miosis Relax the sphincter tone of the bladder, contract the bladder Beta 1 ↓HR, reduce cardiac force of contraction Beta 2 Bronchoconstriction Contracts uterus Inhibit glycogenolysis, which can ↓blood sugar  α-Adrenergic Antagonist They block endogenous catecholamines from binding to α1- and α2-adrenoceptors Selective α-1 blockers : Prazosin, doxazosin, terazosin and Tamsulosin (alpha-1 blockers) MOA: Selective competitive α 1 blocker in blood vessels> decreases peripheral vascular resistant > reduced blood pressure >this induces a reflex tachycardia resulting from the lowered blood pressure For refractory hypertension as add-on therapy  Prazosin It is selectively blocks α1-adrenoceptors Uses: Hypertension Because pt. may experience marked Adverse effects include: postural hypotension and syncope with the first dose, the drug is 1. Nasal stiffness (due to ↑ blood flow to the generally prescribed initially at a very low dose and is titrated to higher dose mucus membrane) depending on the clinical response 2. Orthostatic hypotension (dilatation of veins thereby reducing return of blood to the heart) 3. Tachycardia (reflex increase in sympathetic discharge in response to a decrease in BP)  β-Adrenergic Blockers Action of β-blocker : Block the action Uses: 1. CVDs: hypertension, angina, cardiac of catecholamine at β1- receptor arrhythmias, myocardial infarction and Result in: heart failure 2. Glaucoma (-) chronotropic→↓ HR 3. Acute panic symptoms(Propranolol): (-) inotropic →↓Myocardial contractility ↓sympathetic (β1) and skeletal muscle tremor (β2) ↓BP  Selectivity of some β-Adrenoceptor Antagonist Class Non-selective β– Non-selective β- and Selective β1– Adrenergic α1- Adrenergic Adrenergic Antagonists Antagonists (Block Antagonists (Cardioselective) both β1 and β2) Labetalol /Carvedilol Propranolol/ Nadolol Esmolol/ Metoprolol /Timolol /Atenolol  Nonselective β-blockers Adverse effects ▪ Bronchoconstriction: Blocking β2 receptors in the lungs can cause bronchoconstriction Can worsen COPD and asthma > nonselective β-blockers are contraindicated in COPD or asthma. ▪ Metabolic disturbances: ▪ Fasting hypoglycemia ▪ β-blockers can mask symptoms of hypoglycemia such as tremor, tachycardia, and nervousness.  Nonselective β-blockers Adverse effects ▪ CNS : Lipophilic such as propranolol > many CNS adverse effects > e.g. depression, fatigue, nightmares. Hydrophilic β-blockers (e.g., atenolol), they do not cross the blood–brain barrier. ▪ Coldness of extremities.  Propranolol ▪ Nonselective β-blocker > decreases cardiac output (-ve inotropic and chronotropic) ▪ Therapeutic uses: hypertension, migraine, hyperthyroidism, angina and MI ▪ Pharmacokinetics: ▪ Extensive first-pass metabolism > only 25% bioavailability. ▪ High lipophilicity: Great CNS penetration ▪ Extensive hepatic metabolism, and most metabolites are excreted in the urine. Timolol ▪ Nonselective β antagonists ▪ Timolol reduces the production of aqueous humor in the eye. It is used topically in the treatment of chronic open-angle glaucoma. Cardio selective β-blockers ▪ Atenolol, metoprolol, bisoprolol ▪ Block the β1 receptors selectively minimize the unwanted bronchoconstriction (β2 effect) seen with non-selective β-blockers use in asthma patients. ▪ Therapeutic uses: hypertensive, angina, heart failure. α and β antagonists ▪ Labetalol and carvedilol ▪ Nonselective β-blockers with α1-blocking actions which produce peripheral vasodilation > reduce blood pressure. ▪ Labetalol used as an alternative to methyldopa in the treatment of pregnancy- induced hypertension. ▪ Orthostatic hypotension and dizziness are associated with α1 blockade. Adrenergic neuron antagonists ▪ They act by:​ 1. ↓NA Synthesis ​ ▪ e.g. Carbidopa and α-methyldopa. 2. ↓NA Storage ​ ▪ e.g. Reserpine : block vesicle uptake of NE leading to depletes NE from Adrenergic neurons, used for resistant hypertension.​ 3. ↓NA Release ▪ e.g. Guanthidine (not used clinically)​​